Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA.

BACKGROUND: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. PATIENTS AND METHODS: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). RESULTS: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. CONCLUSIONS: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.

Latent ion tracks were finally observed in diamond.

Injecting high-energy heavy ions in the electronic stopping regime into solids can create cylindrical damage zones called latent ion tracks. Although these tracks form in many materials, none have ever been observed in diamond, even when irradiated with high-energy GeV uranium ions. Here we report the first observation of ion track formation in diamond irradiated with 2-9 MeV C60 fullerene ions. Depending on the ion energy, the mean track length (diameter) changed from 17 (3.2) nm to 52 (7.1) nm. High resolution scanning transmission electron microscopy (HR-STEM) indicated the amorphization in the tracks, in which π-bonding signal from graphite was detected by the electron energy loss spectroscopy (EELS). Since the melting transition is not induced in diamond at atmospheric pressure, conventional inelastic thermal spike calculations cannot be applied. Two-temperature molecular dynamics simulations succeeded in the reproduction of both the track formation under MeV C60 irradiations and the no-track formation under GeV monoatomic ion irradiations.

The Japanese Esophageal Society classification for prediction of superficial esophageal squamous cell neoplasia invasion depth: Validation in a Western population.

BACKGROUND: The Japan Esophageal Society proposed the JES microvessel classification to assess eligibility of early esophageal squamous cell neoplasia (ESCN) for endoscopic resection based on intrapapillary capillary loop assessment. We aimed to assess its diagnostic reproducibility and accuracy in Western ESCN patients. METHODS: Intrapapillary capillary loops on endoscopic images of Western ESCN lesions (n = 113) collected between 2010 and 2022 were assessed by nine endoscopists, including three Japanese expert endoscopists, three Western expert endoscopists, and three residents-in-training, and graded according to the JES microvessel classification where microvessel type A corresponds with normality or low-grade intraepithelial neoplasia, and microvessel types B1, B2, and B3 correspond with high-grade intraepithelial neoplasia or invasion into the lamina propria, muscularis mucosae or superficial submucosa, and deep submucosa, respectively. Outcomes included overall accuracy in predicting ESCN invasion depth and interobserver agreement. RESULTS: Good interobserver agreement was observed among expert endoscopists (Krippendorf's alpha 0.64, 95% CI 0.57-0.70), while agreement was moderate among residents-in-training (Krippendorf's alpha 0.58, 95% CI 0.52-0.72). Overall accuracy of the JES microvessel classification was 53% (95% CI 42-63), 52% (95% CI 41-62), and 44% (95% CI 34-55) for Japanese endoscopists, Western endoscopists, and residents-in-training, respectively. Sensitivity and specificity for vessel type A, B1, B2, and B3 across assessors were 0%-50% and 89%-100%, 55%-64% and 66%-77%, 42%-71% and 60%-76%, and 10%-24% and 92%-97%, respectively. Negative predictive value ranged between 80% and 85% for B3 vessels. CONCLUSION: Overall accuracy of the JES microvessel classification in Western ESCN patients is low, though absence of B3 vessels as assessed by experienced endoscopists may predict superficial ESCN amenable to endoscopic resection. TRIAL REGISTRY: www.trialregister.nl; NL8897 (6-9-2020).

Avaliação on-farm dos níveis de energia na dieta sobre a produção e a composição físico-química de leite de cabras / [On farm evaluation of the energy levels in the diet on the production and physical-chemical composition of dairy goats]

Objetivou-se, com este estudo, avaliar o efeito de dietas com diferentes níveis de energia no consumo de nutrientes, na produção e na composição do leite, no peso corporal e na relação benefício:custo de uma produção de cabras leiteiras. Foram utilizadas nove cabras, distribuídas em quadrado latino triplo 3 x 3. O ensaio teve duração de 60 dias, divididos em três períodos de 20 dias. Avaliaram-se rações completas contendo três níveis de energia: 65%, 70% e 75% de NDT. Os consumos de matéria seca, proteína bruta e matéria mineral foram superiores (P<0,05) nas dietas com maiores níveis de energia em comparação à dieta com 65% de NDT. A produção de leite foi semelhante (P>0,05) nas cabras recebendo dietas contendo 70% e 75% de NDT, todavia foi superior (P<0,05) à produção de leite das cabras recebendo dieta com 65% de NDT. A dieta com 75% de NDT possibilitou maior (P<0,05) peso corporal final, quando comparada com as dietas contendo 65% e 70% de NDT. Não foi observada diferença (P>0,05) para os parâmetros físico-químicos de gordura, lactose, proteína bruta, extrato seco desengordurado, densidade, sais e condutividade do leite. Portanto, cabras alimentadas com níveis de energia entre 70% e 75% de NDT na dieta total aumentam a produção de leite, porém 75% de NDT na dieta proporciona melhor relação benefício:custo, havendo, para cada R$ 1,00 no custo investido na alimentação, R$ 1,52 de retorno financeiro.(AU)

The objective of this study was to evaluate the effect of diets with different energy levels on nutrient intake, milk production and composition, body weight and benefit:cost ratio of a dairy goat production. Nine goats were distributed in a triple 3 x 3 latin square design. The experiment lasted for 60 days, divided into three 20-day periods. Complete rations containing three energy levels were evaluated: 65%, 70% and 75% of TDN. The dry matter intake, crude protein and mineral matter consumption were higher (P <0.05) in the diets with higher levels of energy compared to the diet with 65% of TDN. Milk production was similar (P> 0.05) in goats receiving diets containing 70% and 75% TDN, but these diets produced more milk (P<0.05) than the diet with 65% of TDN. The diet with 75% of TDN allowed a higher (P<0.05) final body weight (P<0.05) when compared to diets containing 65% and 70% TDN. There was no difference (P> 0.05) in the physical-chemical parameters of fat, lactose, crude protein, defatted dry extract, density, salts and conductivity of the milk. Therefore, goats fed with diets of 70% and 75% of TDN in the total diet increased milk production. However, the diet with 75% of TDN provides a better benefit:cost ratio, as for every $ 1.00 in the cost invested, there was $ 1.52 of financial return.(AU)

Interleukin 33 Is Induced by Tumor Necrosis Factor α and Interferon ƴ in Keratinocytes and Contributes to Allergic Contact Dermatitis

Background: Interleukin (IL) 33, a novel member of the IL-1 family, is produced mainly by epithelial cells and endothelial cells in response to various types of stress, including necrosis. The effects of IL-33 on the immune cells involved in allergic contact dermatitis have recently been revealed in vitro. However, in vivo, the induction mechanism and function of IL-33 are not fully understood. Objectives: Our objectives were to investigate induction of IL-33 in keratinocytes and to evaluate the functions of IL-33 and its inducers in a murine model of allergic contact dermatitis. Material and Methods: KERTr cells, a human keratinocyte cell line, were cultured with various cytokines, including tumor necrosis factor (TNF) α and interferon (IFN) ƴ. IL-33 expression was detected using quantitative reverse transcriptase polymerase chain reaction, immunocytochemistry, and Western blotting. The functions of IL-33, TNF- α, and IFN-􀁡 in allergic contact dermatitis were evaluated using a murine model. Results: TNF- α and IFN- ƴ induced expression of IL-33 mRNA and protein in KERTr cells. Blockade of IL-33 attenuated swelling in the ears of the experimental mice. Similar effects were noted for blockade of TNF- α and IFN- ƴ in these mice. Conclusions: TNF- α and IFN- ƴ induce expression of IL-33, and IL-33 produced by keratinocytes contributes to allergic contact dermatitis. Blockade of IL-33, TNF- α, and IFN- ƴ could represent novel and potent strategies to treat allergic contact dermatitis (AU)

Antecedentes: La Interleucina 33 (IL-33), un nuevo miembro de la familia de la IL-1, es producida fundamentalmente por las células epiteliales y endoteliales en respuesta a diferentes estímulos, incluyendo la necrosis. Recientemente se han confirmado los efectos de esta IL sobre las células del sistema inmunológico in vitro en pacientes con dermatitis de contacto, aunque los mecanismos y función in vivo de la IL-33 no son bien conocidos. Objetivos: El objetivo de este estudio fue analizar los factores que podrían inducir IL-33 en queratinocitos y evaluar las funciones de esta citocina y de sus inductores en un modelo murino de dermatitis alérgica de contacto. Métodos: Para ello se cultivaron células KERTr, una línea celular de queratinocitos humanos, en presencia de varias citocinas, incluyendo TNF- α e IFN − ƴ. La expresión de IL-13 se detectó mediante PCR cuantitativa a tiempo real, inmunocitoquímica e inmunobloting. Así mismo se evaluó la función de IL-33, TNF- α, e IFN- ƴ en el modelo murino. Resultados: En cuanto a los resultados obtenidos TNF- α y IFN- ƴ indujeron la expresión de mRNA y expresión de proteína en las células KERTr. El bloqueo de IL-33 atenúa la inflación en la dermatitis de contacto murina. Efectos similares se obtienen mediante el bloqueo de TNF- α y IFN- ƴ. Conclusiones: En conclusión, TNF- α and IFN- ƴ son inductores de la producción de IL-33, y además esta citocina producida por los queratinocitos contribuye a la expresión de dermatitis alérgica de contacto. El bloqueo de no solo IL-33, sino también de TNF- α y IFN- ƴ podría representar una modalidad terapéutica nueva y potente en la dermatitis alérgica de contacto (AU)